This invention relates to new therapeutically useful 2-phenylpyran-4-one derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
It is known that nonselective inhibition of the enzyme cyclooxygenase (COX) prevents the overproduction of prostaglandins associated with inflammation, which are mediated by cyclooxygenase-2 (COX-2) bu., at the same time, deprives tissues of basal levels of prostaglandins necessary for the health of certain tissues mediated largely by cyclooxygenase-1 (COX-1). Non steroidal anti-inflammatory drugs are non-selective inhibitors of COX and for that reason, have side effects of decreased renal blood flow, decreased platelet function, dyspepsia and gastric ulceration.
We have now found that certain 2-phenylpyran-4-one derivatives selectively inhibit COX-2 in preference to COX-1 and are useful in the treatment of COX-2 mediated diseases, such as inflammation, pain, fever and asthma with fewer side effects.
Accordingly the present invention provides a 2-phenylpyran-4-one compound of formula (I): 
wherein
R1 represents an alkyl or xe2x80x94NR4R5 group, wherein R4 and R5 each independently represents a hydrogen atom or an alkyl group;
R2 represents an alkyl, C3-C7 cycloalkyl, pyridyl, thienyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups;
R3 represents a methyl, hydroxymethyl, alkoxymethyl, C3-C7 cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH2xe2x80x94R6 group wherein R6 represents an alkyl group; and
X represents a single bond, an oxygen atom, a sulfur atom or a methylene group;
or a pharmaceutically acceptable salt thereof.
The alkyl groups and moieties such as those present in the alkoxy, hydroxyalkyl, mono- or di-alkylamino groups, mentioned in relation to the groups R1 to R6 are usually xe2x80x9clowerxe2x80x9d alkyl that is containing from 1 to 6 particularly from 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight. Preferred alkyl groups, and where relevant alkyl moieties, include methyl, ethyl, propyl including i-propyl, and butyl including n-butyl, t-butyl and sec-butyl.
In a phenyl group substituted by one or more halogen atoms or alkyl, trifluoroalkyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkyl amino, hydroxyalkyl or hydroxycarbonyl groups, the phenyl ring may be substituted by 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3 substituents, each being independently selected from the possible substituents set out above. The phenyl group (attached to X or the pyran-4-one ring through its 1-position) may be substituted at any of the remaining positions, that is to say the 2, 3, 4, 5 or 6-positions. A phenyl group having more than one substituent may be substituted at any combination of positions. For example a phenyl group having two substituents may be substituted at the 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4 or 3 and 5 positions.
In particular, it is preferred that R2 represents a branched alkyl, C3-C7 (preferably C3, C5 or C6) cycloalkyl, napthyl, tetrahydronaphthyl or indanyl group, an unsubstituted phenyl group or a phenyl group substituted by one or more halogen atoms, alkoxy groups, preferably methoxy groups, and/or alkyl groups, preferably methyl groups. The phenyl group preferably has 1, 2 or 3 substituents, more preferably 1 or 2 substituents. Halogen atoms are preferably selected from fluorine, chlorine and bromine atoms. When R2 as a phenyl group substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups, preferably one of the substitutions is at the 4-position of the phenyl group. When R2 is a phenyl group substituted by one or two halogen atoms at least one of the substitutions is preferably on the 2- or the 4-position.
It is preferred that R1 independently represents an unsubstituted alkyl croup such as methyl, ethyl, propyl or butyl, preferably methyl, or an NH2 group (i.e. PR4 and R5 in the above formula both independently represent an H atom)
It is also preferred that R3 independently represents an unsubstituted alkyl group such as methyl, ethyl, propyl or butyl, preferably methyl, a nitrile group, a hydroxymethyl group, a methoxymethyl group, a difluoromethyl group or a hydroxycarbonyl group.
It is further preferred that X independently represents a single bond, an oxygen atom or a methylene group more preferably a single bond or an oxygen atom.
Specific examples of the 2-phenylpyran-4-one derivatives of the present intention include:
2-(4-methanesulfonylphenyl) -6-methyl-3-phenylpyran-4-one,
3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-p-tolylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-m-tolylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-o-tolylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-(4-trifluoromethylphenyl)pyran-4-one,
3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,4-difluorophenyl)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,5-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4- one,
3-(2,5-difluorophenyl)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,6-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,4-dichlorophenyl)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-fluoro-4-methoxyplenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chloro-3-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chloro-4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6 -methylpyran-4-one,
3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one
3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-cyclohexyl-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylyphenyl)-6- methyl-3-naphthalen-2-ylpyran-4-one,
4-(6-methyl-4-oxo-3-phenyl-4H-pyran-2-yl) benzenesulfonamide,
4-[3 (4-fluorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide,
4-[3-(3,4-dichlorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide,
5-(2,4-difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4-pyran-2-carbontrile
3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one,
3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy) pyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-methoxymethylpyran-4-one,
3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonyl-phenyl) pyran-4 -one,
and anyone of the compounds specifically identified in Table 4, and pharmaceutically acceptable salts thereof.
Of outstanding interest are:
3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4 -one,
3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-chloro-4-methylplenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one,
3-(4-fluorophenoxy)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy) pyran-4-one,
3-2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2,5-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4-one,
3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl)pyran-4-one,
and pharmaceutically acceptable salts thereof.
The present invention also provides processes for preparing a compound of formula (I) which depend on the definition of R3. When R3 is a methyl group, compounds of formula (I) are prepared according to the definition of R1. Thus, compounds of formula (I) in which R3 is a methyl group and R1 is an alkyl or xe2x80x94NR4R5 group in which R4 and R5 are alkyl groups, viz. a 2-phenylpyran-4-one derivative of formula (II): 
wherein R1a is an alkyl or xe2x80x94NR4aR5a group in which R4a and R5a are each independently alkyl groups, and R2 and X are as defined above, which comprises reacting a carbonyl derivative of formula (III): 
wherein R1a, R2 and X are as defined above with an excess of anhydrous acetic acid and polyphosphoric acid at a temperature from 100xc2x0 C. to 150xc2x0 C.
The carbonyl derivative of formula (III) may be obtained by methods well known in the literature (E-A-7148831 WO96/06840; WO96/31509an and DE-204520) or when X represents an oxygen or sulfur atom, by reacting a phenacyl derivative of formula (IV): 
wherein R1a is as defined above and Y represents a chlorine or bromine atom, with a hydroxy or mercapto derivative of formula (V):
HXaxe2x80x94R2 xe2x80x83xe2x80x83(V) 
wherein 2 is as defined above and Xa is an oxygen or sulfur atom.
The reaction between the phenacyl derivative of formula (IV) and the intermediate compound of formula (V) may be carried out by heating a mixture of these two starting materials, optionally in a solvent mixture of methylene chloride, benzene or toluene and water, at a temperature of from 15xc2x0 C. to 30xc2x0 C. and in the presence of a phase transfer catalyst as benzyltriethylamonium chloride.
The carbonyl derivative of formula (III) in which X is other than a sulfur atom, may also be prepared by reacting a thio derivative of formula (VI): 
wherein R1a and R2 are as defined above, and Xb is a single bond, an oxygen atom or a methylene group, with an oxidizing agent, preferably magnesium monoperoxyphthalate or 3-chloroperoxybenzoic acid. The reaction is preferably carried out in an organic solvent such as a mixture of methylene chloride with methanol or ethanol, at a temperature of from 10xc2x0 C. to 40xc2x0 C.
The present invention also provides a process for the preparation of a compound of formula (I) wherein R3 is a methyl group, R1 is an alkyl group, and X is other than a sulfur atom viz. 2-phenylpyran-4-one derivative of formula (VII): 
wherein R1b is an alkyl group and R2 and Xb are as defined above by reacting a mercapto derivative of formula (VIII): 
wherein R1b, R2 and Xb are as defined above with an oxidizing agent, preferably with magnesium monoperoxyphthalate or 3-chloroperoxybenzoic acid
The reaction between the mercapto derivative of formula (VIII) and the oxidizing agent is preferably carried out, as previously disclosed for the compound of formula (VI), in an organic solvent such as a mixture of methylene chloride with methanol or ethanol, at a temperature of from 10xc2x0 C. to 40xc2x0 C.
The present invention additionally provides a process for the preparation of a compound of formula (I) wherein R1 is a xe2x80x94NR4R5 group and R3 is a methyl group, viz. 2-phenylpyran-4-one derivative of formula (IX): 
wherein R2, R4, R5 and X are as defined above by reacting a chlorosulfonyl derivative of formula (X): 
wherein R2 and X are as defined above with an amine of formula (XI):
R4xe2x80x94NHxe2x80x94R5 xe2x80x83xe2x80x83(XI) 
wherein R4 and R5 are as defined above.
This reaction is preferably carried out at a temperature Of from 10xc2x0 C. to 40xc2x0 C.
The chlorosulfonyl derivative of formula (X) may, for example, be prepared by reacting a compound of formula (XII): 
wherein R2 and X are as defined above with chlorosulfonic acid, preferably at a temperature of from 80xc2x0 C. to 120xc2x0 C.
The present invention further provides a process For the preparation of a compound of formula (I) wherein R3 is a methyl group and R1 is a group wherein R4 and R5 are hydrogen, viz, the 2-phenylpyran-4-one derivative of formula (XIII): 
wherein R2 and X are as defined above by debenzylation of the corresponding N,N-dibenzyl derivative of formula (XIV): 
wherein R2 and X are as defined above.
The debenzylation is preferably carried out with an excess of trifluoroacetic, sulfuric or methanesulfonic acid at a temperature of from 0xc2x0 C. to 120xc2x0 C.
The intermediate of formula (XIV) may be prepared according to the above processes using appropriate starting materials wherein R4 and R5 (or R4a and R5a) both represent benzyl groups.
The intermediate of formula (IV) and (VI) used in the preparation of the compounds of the invention may be prepared by methods disclosed in the literature, for example, in M. F. Saettone, J. Org. Chem. 31, p 1959 (1966) and WO-9606840.
The intermediate compounds of formulae (VIII) and (XII) may be prepared by the same process disclosed for the preparation of compounds of formula (II), with the appropriate starting materials.
The 2-phenylpyran-4-one derivatives of formula (I) wherein R3 is other than a methyl group, can be prepared by processes which are represented in the following scheme: 
As can be seen in the scheme, 2-phenylpyran-4-one derivatives of formula (I) wherein R3 is other than a methyl group, viz. compounds of formulae (XVII), (XVIII), (XIX), (XX), (XXI), (XXII) and (XXIV), are prepared from compounds of formula (I) in which R3 is a methyl group, viz. compound of formula (XV), which processes of preparation have been disclosed above. In a first stage, compounds of formula (XV) are treated with an oxidizing agent as selenium dioxide in an organic solvent as tetrahydrofuran or dioxan, in a pressure vessel and at a temperature from 100xc2x0 C. to 190xc2x0 C. The corresponding aldehyde of formula (XVI) is obtained, which is used as starting material to obtain the compounds of formula (I) with R3 other than a methyl group.
The compounds of Formula (I) wherein R3 is a hydroxycarbonyl group, viz. compound of formula (XVII), are prepared from the corresponding aldehyde (XVI) by reaction with an oxidizing agent as pyridinium dichromate or manganese dioxide in an organic solvent as N,N-dimethylformamide or ethanol at a temperature between xe2x88x925xc2x0 C. and 35xc2x0 C. The obtained compounds (XVII) are used as starting materials to obtain compounds of Formula (I) wherein R2 is a trifluoromethyl group, viz. compound of formula (XVIII). The reaction is carried out by reaction of compounds (XVII) with a mixture of sulphur tetrafluoride and hydrogen fluoride, optionally in the presence of an organic solvent as methylene chloride, in a pressure vessel, and at a temperature from 20xc2x0 C. to 140xc2x0 C.
The compounds of formula (I) wherein R3 represents a hydroxymethyl group viz. compounds of formula (XIX) are prepared by reduction of compounds (XVI) with a boron or aluminium hydride, preferably sodium borohydride in a solvent as methanol or ethanol and at a temperature from 10xc2x0 C. to 40xc2x0 C. Further reaction of compounds (XIX) with an appropriate halide of formula (XXIII):
Zxe2x80x94R7 xe2x80x83xe2x80x83(XXIII) 
wherein Z represents a chlorine, bromine or iodine atom and R7 represents an alkyl, C3-C7 cycloalkyl or benzyl group, provide the compounds of formula (I) wherein R3 is an alkoxymethyl, C3-C7 cycloalkoxymethyl or benzyloxymethyl group viz. compounds of formula (XX). The reaction is carried out in an organic solvent such as acetone, N,N-dimethylformamide or tetrahydrofuran in the presence of sodium or potassium hydride or amide, and at a temperature between 20xc2x0 C. and 120xc2x0 C.
Also aldehydes of formula (XVI) are used as starting material to obtain compounds of formula (I) wherein R3 is a nitrile group, viz. compounds of formula (XX:). The reaction is carried out n a first stage by treatment of aldehydes (XVI) with hydroxylamine hydrochloride and formic acid at a temperature from 80xc2x0 C. to 120xc2x0 C. The resulting oxime derivative is isolated and heated with an excess of acetic anhydride at a temperature between 100xc2x0 C. to 180xc2x0 C.
The compounds of formula (I) wherein R3 represents a difluoromethyl group, viz. compounds of formula (XXII), are prepared from aldehydes of formula (XVI) by reaction with a fluorinated reagent as diethylaminosulfur trifluoride, or a mixture of sulfur tetrafluoride-hydrogen fluoride, optionally in the presence of an organic solvent as methylene chloride, benzene or toluene and at a temperature from 0xc2x0 C. to 130xc2x0 C.
The 2-phenylpyran-4-one derivatives of formula (I) in which R3 is a CH2xe2x80x94R6 croup, viz. compounds of formula (XXIV), are also prepared from aldehydes of formula (XVI) in a two stages process. In the first stage, the aldehyde (XVI) is reacted with a triphenylphosphine derivative (XXV) in the presence of a solvent as dioxane, dimethoxyethane or tetrahydrofuran at a temperature from 15xc2x0 C. to the boiling point of the solvent. The resulting compound is hydrogenated in the second stage of the process in the presence of a catalyst as palladium or activated carbon. The reaction is carried out in the presence of a solvent as methanol, ethanol or ethyl acetate at a temperature from 15xc2x0 C. to 40xc2x0 C.
The 2-phenylpyran-4-one derivatives of formula (I) in which there is the presence of a basic group, can be converted by methods know per se into pharmaceutically acceptable salts, preferably acid addition salts by treatment with organic or inorganic acids as fumaric, tartaric, succinic or hydrochloric acid. Also, 2-phenylpyran-4-one derivatives of formula (I) in which R3 represents an hydroxycarbonyl group, may be converted into pharmacologically acceptable salts with, for instance, alkali metals such as sodium or potassium by reaction with an alkali metal hydroxide.
The following biological tests and data further illustrate this invention.
COX-1 and COX-2 activities in human whole blood
Fresh blood from healthy volunteers who had not taken any non-steroidal ante-inflammatory drugs for at least 7 days prior to blood extraction was collected in heparinized tubes (20 units of heparin per ml). For the COX-1 activity determination, 500 xcexcl aliquots of blood were incubated with either 5 xcexcl vehicle (dimethylsulphoxide) or 5 xcexcl of a test compound for 1 h at 37xc2x0 C. Calcium ionophore A23187 (25 xcexcM) was added 20 min before stopping the incubation. Plasma was separated by centrifugation (10 min at 13000 rpm) and kept at xe2x88x9230xc2x0 C. until TXB2 levels were measured using an enzyme immunoassay kit (ELISA). The effect of the compounds were evaluated by incubating each compound at five to six different concentrations with triplicate determinations. IC50 values were obtained by non-linear regression using InPlot, GraphPad software on an IBM computer.
For the COX-2 activity determination, 500 xcexcl aliquots of blood were incubated in the presence of LPS (10 xcexcg/ml) for 24 h at 37xc2x0 C. in order to induce The COX-2 expression (Patriagnani et al., J. Pharm. Exper. Ther. 271; 1705-1712 (1994)). Plasma was separated by centrifugation (10 min at 13000 rpm.) and kept at xe2x88x9230xc2x0 C. until PGE2 levels were measured using an enzyme immunoassay kit (ELISA). The effects of inhibitors were studied by incubating each compound (5 xcexcl aliquots) at five to six different concentrations with triplicate determinations in the presence of LPS for 24 hours. IC50 values were obtained by non-linear regression using InPlot, GraphPad software on an IBM computer.
Anti-inflammatory activity (adjuvant arthritis)
Male Wistar rats weighing 175-200 g with free access to food and water were used. On day 0, the animals received an intraplantar injection of a suspension of Mycobacterium tuberculosis in paraffin oil (0.5 mg/rat) on the left hind paw. A group of nonarthritic control rats were injected with paraffin oil alone. On days 11 and 14 after induction of arthritis, the volume of the hind paw of each rat was measured using a water plethysmograph. Animals whose paw volumes increased during that time were selected. Rats were distributed into groups of 8 having equal mean paw volumes and an approximately equal standard deviation
Test compounds were administered p.o. once daily for 7 days (days 14-20). Nonarthritic and arthritic control rats received vehicle alone for 7 days. The hind paw volumes were measured 20 h after the last dose (on day 21). The body weight was determined every second day.
The results were expressed as the percentage of inhibition of inflammation (paw volume) for each treatment group, considering both the arthritic and nonarthritic vehicle controls. The ANOVA tests was used for statistical studies.
Ulcerogenic activity
Animals: Male Wistar rate (Interfauna, U.K., Ltd.) weighing about 150-175 g were used. Animals were maintained on a 12:12 hour light-dark cycle (lights on at 7:00 am) at room temperature (22xc2x11xc2x0 C.). Food and water were allowed ad libitum.
Procedure: The compounds were administered by the oral route once a day for 4 consecutive days. The body weight of each rat was assessed every day before drug administration. The animals were anesthesized 24 h after the last dosing and 1 ml of blood was extracted by cardiac puncture using heparin (10 U/ml) as anticoagulant. The percentage of hematocrit was measured. The intestines were removed, opened longitudinally and gently washed. The macroscopic severity of the intestinal erosions was assessed using a parametric scale, evaluating the number of the perforated and non-perforated intestinal ulcers by means of a lesion index ranging from 0 to 3 (0:no ulcers, 1: less than 10 ulcers, 2:10-25 ulcers to 3: greater than 25 ulcers). No gastric ulcers are observed using this protocol.
The treatments were randomized in each experiment. The results were compared with those obtained in the vehicle-treated group using the ANOVA test.
Results
The results obtained from the biological assays are shown in Table 1, 2 and 3.
As shown in Table 1, the 2-phenylpyran-4-ore derivatives of formula (I) are potent and selective COX-2 inhibitors whereas the reference compound indomethacin is as equipotent as COX-2 and COX-1 inhibitor. Due to their low COX-1 inhibitory activity, the compounds of formula (I) present an importantanti-inflammatory activity (see Table 2) and the benefit of significantly less harmful side effects than the non-steroidal anti-inflammatory drugs commonly used (e.g. gastrointestinal toxicity (see Table 3), renal side-effects, reduced effect on bleeding times and asthma induction in aspirin-sensitive subjects).
Thus the compounds of the invention are preferably selective inhibitors of mammalian COX-2, for example human COX-2. The compounds of the invention also preferably have low inhibitory activity toward mammalian COX-1, for example human COX-1. Inhibitory activity can typically be measured by in vitro assays, or example as described above.
Preferred compounds of the invention have an IC50 value for COX-2 of less than 5 xcexcm, preferably less than 3 more preferably less than 2.5 xcexcm. Preferred compounds of the invention also have an IC50 value for COX-1 of greater than 10 xcexcM, preferably greater than 20 xcexcM. As an indicator of selectivity for inhibition of COX-2 over COX-1, the ratio of COX-1/COX-2 IC50 values is preferably greater than 20, 30 or 50, more preferably greater than 80, 90 or 100.
The present invention further provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the prevention of colorectal cancer or neurodegenerative diseases.
The present invention further provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of pain,, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the prevention of colorectal cancer or neurodegenerative diseases.
The compounds of formula (I) are useful for relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhoea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, bursitis, tendinitis, injuries, following surgical and dental procedures and arthritis including rheumatoid arthritis, osteoarthritis, gouty arthritis, spondyloarthopathies, systemic lupus erythematosus and juvenile arthritis and bone resorption. They may also be used in the treatment of skin inflammation disorders such as psoriasis, eczema, burning and dermatitis. In addition, such compounds may be used for the prevention of colorectal cancer.
The compounds of formula (I) well also inhibit prostanoid-induced smooth muscle contraction and therefore may be used in the treatment of dysmenorrhoea, premature labour, asthma and bronchitis.
The compounds of formula (I) can be used as alternative to conventional non-steroidal anti-inflammatory drugs, particularly where such non-steroidal anti-inflammatory drugs way be contraindicated such as the treatment of patients with gastrointestinal disorders including peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, Crohn""s disease, inflammatory bowel syndrome and irritable bowl syndrome, gastrointestinal bleeding and coagulation disorders, kidney disease (e.g. impaired renal function), those prior to surgery or taking anticoagulants, and those susceptible to non-steroidal anti-inflammatory drugs induced asthma.
The compounds can further be used to treat inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin""s disease, scleroderma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet""s syndrome, polymyositis, hypersensitivity, conjunctivitis, gingivitis, myocardial ischaemia and stroke.
Compounds of the present invention are inhibitors of cyclooxygenase-2 enzyme and are thereby useful to treat the cyclooxygenase-2 mediated diseases enumerated above. These compounds can further be used for the prevent on of neurodegenerative diseases such as Alzheimer""s disease.
Accordingly, the 2-phenylpyran-4-one derivatives of formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and/or salts thereof, may be used in a method of treatment of disorders of the human body which comprises administering to a patient requiring such treatment an effective amount of a 2-phenylpyran-4-one derivative of formula (I) or a pharmaceutically acceptable salt thereof.
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, as least a 2-phenylpyran-4-one derivative of formula (I) or a pharmacologically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
Preferably the compositions are made up in a form suitable for oral, topical, nasal, inhalation, rectal, percutaneous or injectable administration.
The pharmaceutically acceptable excipients which are admixed with the active compound, or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.
Compositions so this invention are preferably adapted for injectable and per os administration. In this case, the compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.
The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a, pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in pyrogen free aqueous media or other appropriate parenteral injection fluid.
Effective doses are normally in the range of 10-600 mg of active ingredient per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
The invention is illustrated by the following Examples, which do not limit the scope of the invention in any way.